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Treating latent TB infection –an update
David Holland, MD, MHSDuke University Medical CenterMedical Consultant, North Carolina TB Program
Disclosures
No relevant financial disclosures
Other than isoniazid, none of the drugs I mention are FDA‐approved for any of the indications in this presentation.
John Snow
1954 cholera outbreak in London
Identified a single water pump as the source of the outbreak
Epidemic abated after the pump handle was removed
Later showed that the water company was pumping sewage from the Thames to the affected area
$9.56 at Home Depot
TB in the U.S.
Active TB (2010 data)11,182 cases3.6 cases per 100,000547 deaths (2009)
CDC. Reported Tuberculosis in the United States, 2010. Atlanta, GA: U.S. Department of Health and Human Services, CDC, October 2011.
1999‐2000 National Health and Nutritional Examination Survey
LTBI prevalence (TST > 10mm):Bennett DE. Am J Respir Crit Care Med. 2008 Feb 1;177(3):348‐55
4.2% = 11,213,000 persons infected1.8% in U.S.‐born18.7% in foreign‐born
25.5% reported prior history of TB/LTBIOnly 13.2% reported prior treatment (about half)
Goal for 2010* = incidence of 1 per 1,000,000 for active cases (MMWR. 1989 Jan 13;38(1):1‐4)
Requires LTBI prevalence of 1% or lessStyblo K. Bull Int Union Tuberc Lung Dis 1990;65:49–55
*Per CDC’s Healthy People 2010. TB is not mentioned in Healthy People 2020.
Why do we treat LTBI?
Prevent deathsPeople still die from TB
Prevent morbidityEspecially in kids
Save moneyIt costs less to treat LTBI than active TB
Why do we treat LTBI?
Prevent deathsPeople still die from TB
Prevent morbidityEspecially in kids
Save money
(But lives are also important.)
What does treating LTBI cost?
Several costs to consider:DrugsNursing timeMonitoringToxicityDOT
But also savings:Cases avertedSecondary cases averted
(Remember: Infectious diseases are infectious)
LTBI treatment – susceptible diseaseRecommended regimens
Drug Frequency Duration Issues Abbrev
Isoniazid Daily9 months(6 months)
Long duration, poor adherence 9H
Isoniazid Twice weekly9 months(6 months)
Directly‐observed, long duration 9H‐DOT
Rifampin Daily 4 months Drug interactions 4R
Other regimens
Isoniazid + rifapentine Once weekly 3 months Experimental, DOT 3HP
Rifampin + pyrazinamide
Daily or 2x/week
2 months Potentially fatal 2RZ
Isoniazid + rifampin Daily 3 months Not in U.S.
recommendations 3HR
Isoniazid for LTBI
Dozens of studies on efficacy
Cheap
Current standard of care
Nine months recommended for all groups
Isoniazid
Risk reduction from various durations of INH in patients with LTBI.Bull.World Health Organ. 1982;60(4):555‐64.
Duration (months)
Group 3 6 12
Overall 21% 65% 75%
Completer/compliers 31% 69% 93%
A subsequent cost‐effectiveness analysis showed 6H to be more cost‐effective than 12H.Snider DE. JAMA. 1986 Mar 28;255(12):1579‐83.
Isoniazid for nine months
Comstock GW. Int J Tuberc Lung Dis. 1999 Oct;3(10):847‐50.
Problems with isoniazid
Poor adherenceCompletion rates < 50% in some studies
Toxicity1‐2% in adults
Rifamycins
Inhibit DNA‐dependent RNA polymeraseActive against non‐replicating bacteriaIsoniazid only active against replicating bacteria
Active against a broad array of bacteria (including MTB)
Examples:RifampinRifabutinRifapentine
Isoniazid
Rifampin
Rifapentine
Rifampin – Adherence and toxicity
Completion rates much higherUp to 80% in one study
Substantially less hepatotoxicity0.3% versus 1.4% for INH in one study
Rifamycins – other toxicity
Hypersensitivity syndrome“Flu‐like” symptoms (fever, malaise, myalgias)Not well‐defined
Anemia, thrombocytopenia
Both more common with intermittent doses
Rifamycins – drug interactions
Oral anticoagulantsOral contraceptivesCyclosporineGlucocorticoidsItraconazoleKetoconazoleMethadoneMidazolam or triazolamPhenytoinQuinidineTheophyllineVerapamilβ‐Adrenergic blocking agentsChloramphenicolClarithromycinDapsone
DiazepamDigoxin (oral)DiltiazemDisopyramideDoxycyclineFluconazoleHaloperidolLosartan potassiumNifedipineNortriptylineSulfonylureasTacrolimusTocainide
Rifamycins – drug interactions
Check everything!
Oral contraceptives, coumadin, azole antifungals, and anti‐rejection agents are common offenders
Many antiretroviral agents (for HIV treatment) interact – always check everything
Consult an expert for any interaction, especially when HIV meds are involved
Rifampin – Efficacy
One study
679 Chinese men with silicosis randomized to one of three groups:
Rifampin for threemonths (3R)Rifampin plus INH for three months (3HR)Isoniazid for six months (6H)Placebo
Hong Kong Chest Service. Am Rev Respir Dis. 1992 Jan;145(1):36‐41.
Rifampin – Efficacy
Development of active TB:3R: 12%3HR: 16%6H: 14%Plac: 23%
Risk reduction for 3R: 52%Risk reduction for 6H: 61%(Pts all had silicosis, so rates were much higher)
Hong Kong Chest Service. Am Rev Respir Dis. 1992 Jan;145(1):36‐41.
So where do we get “4 months” from?
6H < 12H ~ 9H, so 9H is the recommendation
3R ~ 6H < 9H, so….4R is the recommendation
In other words, we have no direct efficacy data (yet) for four months of rifampin.
Rifapentine
Similar to rifampin, but a longer half‐life
Initially approved for once‐weekly therapy of active TB in the continuation phase
Three studies of efficacy for treatment of LTBI (once per week in combination with isoniazid)
Rifapentine – efficacy
399 household contacts in Brazil
Two groups:Rifampin/pyrazinamide daily for two months (2RZ, control)Rifapentine/isoniazid weekly for three months (3HP)
Trial stopped early due to excess toxicity in Rif/PZA arm (the control group)
Not enough power to draw any conclusionsOnly four cases developed
Three in 3HP armOne in 2RZ arm
Schechter M. Am J Respir Crit Care Med. 2006 Apr 15;173(8):922‐6.
Rifapentine – efficacy1150 HIV+ patients in South Africa
Average CD4 between 500‐600
Four groups:Rifapentine/isoniazid weekly for 3 months (3HP)Rifampin/isoniazid 2x/week for 3 months (3HR)Isoniazid daily throughout study (HHH…)Isoniazid daily x 6 months (6H, control)
Patients followed for 5 yearsMartinson N et al. 39th IUATLD World Conference on Lung Health, late breaker abstract, Paris, 2008.
South Africa study – resultsNo significant difference in efficacy between groupsContinuous INH better years 1 & 2
Declined due to dropouts and toxicity years 3 & 4
Regimen PY of follow up RR Comments
3HP 1242 1.05 1 MDR, 1 rif resistant3HR 1279 1.06HHH….. 582 0.71 1 MDR6H 1182 Ref
Martinson N et al. 39th IUATLD World Conference on Lung Health, late breaker abstract, Paris, 2008.
TB Trials Consortium Study 26 (PREVENT‐TB)
8,000 “high‐risk” patients in U.S., Brazil, SpainContacts, convertersHIV+ (very few)Children 2 years and older
Two arms:Rifapentine/isoniazid weekly for 3 months by DOT (3HP‐DOT)Isoniazid daily for 9 months self‐administered (9H‐SAT)
Study 26 – results
Both arms similar efficacy15 cases (0.43%) in 9H arm7 cases (0.19%) in 3HP arm
Completion much higher with 3HP (80%)
Toxicity slightly higher with 3HP (5% vs 3% in 9H)Hepatotoxicity the same“Excess” toxicity was hypersensitivity
(There is some evidence that it may have been over‐reported.)
Study 26 – Some caveats
DOT was used in the study, so there is no data on completion rates for self‐administered therapy
Ten pills once per week – adherence could be very different
Limited data on HIV+ patients
No data yet on children <2 years
The practical stuff: Shorter course regimens for treating LTBI
Regimen 1 – 4R
Rifampin 600 mg daily x 4 months6 months in children
Most experience
Can be used in children
No data on efficacy
Can be self‐administered
No intermittent option
Regimen 2 – 2RZ
Rifampin 600 mg plus pyrazinamide 15‐25 mg/kg daily for two months
Good data on efficacy
Kills people – not recommended
Regimen 3 – 3HR
Rifampin 600 mg plus INH 300 mg for 3 months
Commonly used in Europe
Limited data on efficacy
Can be self‐administered
No intermittent option
Regimen 4 – 3HPRifapentine 900 mg plus INH 900 mg once per week for 3 months (12 doses)
Limited experience, especially with HIV+ patients
Solid data on efficacy
3HP – CDC Recommendations (hot off the press)
Equal alternative to 9H for the following:ContactsRecent convertersOld, healed (Class IV) TB
Adults and children ≥12Can be used in children 2‐11 on a “case by case” basis
HIV+ if healthy and on no ARVs
Should not be used in pregnant women
Should be given by DOT
Monitoring
All patients on LTBI treatment with any regimen should be clinically monitored at least monthly.
Rifampin only: Consider liver enzymes and CBC for the anyone meeting the following criteria:
HIV+Regular alcohol useUnderlying liver disease
If the patient is taking INH, use standard INH monitoring procedures, too.
Check for drug interactions
Look them up!
If the patient is HIV+ and on antiretrovirals, speak to one of the TB medical consultants and/or the patient’s HIV physician before starting rifampin or rifapentine
“All of this is great, but aren’t these new drugs more expensive?”
Well, yes.
But if they prevent more TB, they may still save money.
Cost‐effectiveness of LTBI treatment – a model
Markov model of LTBI treatment
Cohort of TB contacts at otherwise low risk of activation (i.e., HIV‐negative, etc.)
Four regimens considered:9H3HP (SAT and DOT)4R
Cost of LTBI drugs1
Drug Per pill Per doseIsoniazid 300 mg $0.03 $0.03Rifampin 300 mg $0.42 $0.84Rifapentine 150 mg $2.22 $13.32Pyridoxine 25 mg $0.01 $0.01
1NC Public Health Pharmacy Pricing
Cost of LTBI drugs1
Drug Per pill Per doseIsoniazid 300 mg $0.03 $0.03Rifampin 300 mg $0.42 $0.84Rifapentine 150 mg $2.22 $13.32Pyridoxine 25 mg $0.01 $0.01
1NC Public Health Pharmacy Pricing
Other costs
Monitoring = $26.52 per visit
DOT = $24.08 per dose
Cost of severe toxicityLabs = $164.80Hospitalization (1%) = $5,537.84
Known knowns and known unknowns
9H 3HP‐DOT 3HP‐SAT 4REfficacy 93% 93% 93% 93%Treatment‐limiting toxicity 1.4% 5% 5% 0.35%
Adherence 53% 90% 87% 80%Total therapy cost (incl. monitoring) $250 $524 $241 $207
9H = Isoniazid daily for 9 months (SAT)3HP = Isoniazid + rifapentine weekly for 3 months4R = Rifampin for 4 month (SAT)
DOT = directly‐observedSAT = self‐administered
A few other assumptions
Lifetime risk of activation 6%Number of secondary cases/case 1.2
Cost of active TB6 months $13,0009 months $13,783
4R
3HP‐SAT
9H
3HP‐DOT
No treatment
ICER = $3,656
ICER = $129,076
22.60
22.61
22.62
22.63
22.64
22.65
22.66
22.67
22.68
$250 $500 $750 $1,000 $1,250 $1,500 $1,750
Effe
ctiv
enes
s (Q
ALY
S)
Cost
“Better”
“Worse”
Definition
Dominate = be less expensive and more effective than (another regimen)
Sensitivity analysis – continued
Efficacy*4R can be 17% less effective than 9H and still dominate 9H
*Assume base case values for other parameters
How wrong can we be? (Sensitivity analysis)
Adherence*
3HP‐SAT3HP‐SAT adherence can be as low as 70% (base‐case 87%) and still dominate 9H3HP‐SAT adherence can be as low as 67% and still dominate 3HP‐DOT
*Assume base case values for other parameters
Higher risk patients
3HP‐DOT dominates all other regimens for HIV+ patients not on HAART
However, data on HIV+ patients is limited
SummaryRifamycins allow for shorter treatment of LTBI with better completion rates.
Rifampin (4 months) is well‐tolerated but has limited data on efficacy
Rifapentine (with INH for 3 months) has good data on efficacy but should be given via DOT.
Shorter course regimens without DOT are more effective and less expensive than isoniazid monotherapy
DOT may be justified for high‐risk patients.
Questions?
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